The simultaneous discovery of genetic linkage between familial Alzheimer's disease (FAD) and chromosome 21 DNA markers in four large FAD pedigrees combined with the mapping of the amyloid beta protein precursor gene (APP) to the same chromosome suggested in 1987 that an FAD gene locus may have been identified. When the same four pedigrees were tested directly for linkage to APP, the occurrence of at least one crossover in each family along with other reports of non-linkage dashed the hope that a gene responsible for FAD had been isolated. Two recent findings have rekindled interest in the potential role of the APP gene in the etiology and have consequently, prompted the need for a careful re-evaluation of the APP gene in FAD. First, non-allelic genetic heterogeneity of FAD was demonstrated, implying that while a subset of pedigrees are chromosome 21-linked, others, and in particular, those with late age of onset are either linked to loci residing elsewhere in the genome or involve an enviromental origin. Since families not linked to chromosome 21 could effectively mask overall genetic linkage to APP, it remains possible that APP represents the site of a defect in some families. This possibility has been strengthened by the recent discovery of an apparent missense mutation in exon 17 of APP in five FAD pedigrees, and a separate mutation in this same exon in patients from three pedigrees with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). The FAD-related mutation in exon 17 disrupts a putative iron-response element (IRE) in the C-terminal BetaA4 region of APP RNA which is homologous with those found in ferritin and transferrin receptor messages. These elements have been shown to interact with specific binding proteins which regulate the level of translation in response to iron concentration. By analogy, the putative IRE in APP RNA may play a similar role. This possibility and the effects of a mutation on the stability of this structure need to be addressed. In summary, the strong likelihood that APP mutations are responsible for some forms of AD and the insight that they would provide on the basic etiology of this disorder indicate the need for a careful assessment of 1. the extent to which defects in the APP gene are associated with AD, and 2. the potential consequences of a known mutation in the FAD gene with respect to AD pathology.